Heterotopic ossification (HO) is characterized by the formation of ectopic bone in soft tissues, such as the fibrous tissue adjacent to joints. It is most commonly associated with trauma, such as spinal cord injury, brain injuries, head injuries, burns, fractures, muscle contusions, combat-related trauma and surgery (especially joint arthroplasty). In addition, HO may occur in patients that are on neuromuscular blockade to manage adult respiratory distress syndrome and in patients with non-traumatic myelopathies. In rare cases, HO may present as part of a hereditary disease and is sometimes associated with lower motor neuron disorders. The consequences of HO may include, inter alia, joint contracture and ankylosis, pain, spasticity, swelling, fever, neurovascular compression, pressure ulcers, and significant disability. Lesions range from small, clinically insignificant foci to massive deposits throughout the body.
NSAIDs, such as indomethacin, can be effective in the prevention of HO if treatment is started early and preoperative radiation may be used to prevent HO after total hip or knee arthroplasty. Combined postoperative radiotherapy and indomethacin has also been suggested to be effective at preventing HO. Unfortunately both radiation therapy and NSAID treatment have significant limitations and may result in serious side effects (see Baird, et al., J. Ortho. Surg. Res. 4:12 (2009)).
There are currently no generally effective treatments for ectopic bone formation due to genetic diseases. Areas of well-circumscribed HO can sometimes be surgically removed with successful long-term results but resection of diffuse lesions usually leads to recurrences or complications. Successful functional repositioning of a joint after the development of a contracture from HO may also occasionally be possible. However, treatment options are very limited and these diseases are generally severely disabling.
Recent analyses have suggested that the cellular origin for ectopic bone formation may be mesenchymal progenitor cells. The differentiation of these cells into osteogenic lineages is induced by a pathological microenvironment in soft tissues outside the skeletal tissue, which includes inflammation. Recent reports suggest that drugs that act as antagonists of the Hedgehog signaling pathway (which is essential for proper embryonic development and is believed to play a role in the development of some cancers) may be effectively used to prevent or treat HO as well as other pathological conditions characterized by ectopic calcification (see e.g., US 2014/0220154). Further development of treatment methods using Hh pathway antagonists and other agents is clearly warranted.